Exercise is a highly effective therapy for prevention and treatment of numerous diseases, including metabolic syndrome and diabetes. However, there is a fundamental gap in understanding the precise molecular mechanisms that mediate the beneficial effects of exercise. The long-term objective of this project is to gain novel insigh into how exercise signals to the transcriptional circuits that govern skeletal muscle substrate/energy flux with the ultimate goal of developing novel therapies for metabolic and myopathic diseases. Exciting preliminary studies implicate the exercise-inducible transcription factor Kruppel-like factor 15 (KLF15) as a novel regulator of muscle metabolism and exercise adaptation. Further data strongly indicate that a major mechanism by which KLF15 induces direct targets is via interaction with the coactivator p300. Finally, physiologic glucocorticoid receptor (GR) activation during exercise mediates induction of KLF15 and key glucocorticoid (GC) inducible genes involved in substrate utilization are KLF15 dependent. Based on this rationale, this proposal will test the central hypothesis that skeletal muscle KLF15 is essential for metabolic adaptation in vivo and functions as a critical effector of GC signaling during exercise. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: (1) To elucidate the physiologic consequences of manipulating KLF15 levels in a muscle-specific fashion; (2) To determine the precise molecular basis for KLF15's ability to induce target genes; and (3) To define the importance of the GC-KLF15 axis in muscle physiology (exercise adaptation) and disease (atrophy). Under Aim 1, novel mouse models harboring muscle-specific deletion/overexpression of KLF15 (which have been created in the applicant's laboratory) will be characterized using physiologic/metabolic assays to unequivocally establish KLF15's tissue- intrinsic role. Under Aim 2, detailed mechanistic studies will be undertaken to dissect the importance of the KLF15-p300 interaction in gene regulation. Under Aim 3, the role of KLF15 in GC-mediated exercise adaptation and muscle atrophy will be rigorously tested using an array of physiologic and molecular approaches. These studies have the potential to significantly change the view of GC signaling in muscle. Feasibility of all physiologic and molecular assays has been clearly established in the hands of the applicant and expert investigative team (evidenced by published/preliminary studies). The approach is innovative because it employs novel in vivo models (muscle-specific KLF15 gain/loss of function) to provide a new understanding of the poorly understood adaptive/ergogenic effects of GC signaling. The proposed research is significant because it vertically advances our understanding of the neurohormonal control of skeletal muscle plasticity and provides foundation for novel therapies that can potentiate the beneficial effects of exercise and combat metabolic and myopathic diseases.